The emergence of bacterial resistance to a number of antimicrobial agents such as beta-lactam antibiotics, macrolides, quinolones, and vancomycin is becoming a major worldwide health problem. (Cohen, M. L. Antimicrobial resistance: prognosis for public health. Trends Microbiol. 1994, 2, 422-425). The most significant problem in clinical practice is the increase in incidence of methicillin-resistant Staphylococcus aureus (MRSA) strains. At present, the only effective treatment for multiple resistant MRSA infections is vancomycin. However, there are recent reports of emerging vancomycin resistance in some MRSA isolates. Another group of clinically relevant multiple drug resistant bacteria that have emerged recently are the Enterococci. The emerging resistance of the important community acquired pathogen Streptococcus pneumoniae to penicillin and other antibacterials is also becoming a worldwide health problem. Multi drug-resistant strains of Mycobacterium tuberculosis have surfaced in several countries including the United States. The emergence and spread of resistant nosocomial and community-acquired pathogens is generating a great threat to public health worldwide. There is an urgent need to discover new agents to treat patients infected with multidrug-resistant bacteria. The present invention addresses this need.
New thiazolyl peptide antibiotics, (designated herein as nocathiacin I, II and III, or collectively as nocathiacin) having inhibitory activity at the nanomolar level against Gram-positive bacteria (e.g. multiple drug resistant Enterococcus faecium), are described. The novel antibiotics described herein were isolated from cultured broth of Nocardia sp. ATCC-202099. Known members of the thiazolyl peptide class of antibiotics such as thiostrepton and nosiheptide, and glycothiohexide-.alpha. have been reported to exhibit potent antimicrobial activity against Gram-positive bacteria in vitro, with no reported activity in vivo. The novel antibiotics disclosed herein exhibit in vivo efficacy in a systemic Staph. aureus infection model in mice.
Nocathiacin I has been previously described by J. E. Leet et al (U.S. Provisional Patent Application Serial No. 60/093,021 filed Jul. 16, 1998) commonly owned by Applicant herein, and Sasaki, T. et al, J. of Antibiotics 51, No. 8, pp. 715-721 (published Aug. 25, 1998). The novel nocathiacin antibiotics of this invention are related to but clearly distinguishable from nosiheptide (Prange T. et al., J. Am Chem Soc. 99, 6418 (1977); Benazet, F. et. al. Experientia 36, 414 (1980); Floss, H. G. et al., J. Am Chem Soc. 115, 7557 (1993); glycothiohexides (Steinberg, D. A. et al, J. Antibiot. 47, 887 (1994); M. D. Lee et al, J. Antibiot. 47, 894 (1994); M. D. Lee et al, J. Antibiot. 47, 901 (1994); U.S. Pat. No. 5,451,581, 1995), and Antibiotic S-54832A (U.S. Pat. No. 4,478,831, 1984).